Circulating Exosomal circRNAs Contribute to Potential Diagnostic Value of Large Artery Atherosclerotic Stroke

Large artery atherosclerotic (LAA) stroke is closely associated with atherosclerosis, characterized by the accumulation of immune cells. Early recognition of LAA stroke is crucial. Circulating exosomal circRNAs profiling represents a promising, noninvasive approach for the detection of LAA stroke. Exosomal circRNA sequencing was used to identify differentially expressed circRNAs between LAA stroke and normal controls. From a further validation stage, the results were validated using RT-qPCR. We then built logistic regression models of exosomal circRNAs based on a large replication stage, and receiver operating characteristic (ROC) curves were constructed to assess the diagnostic efficacy. Using exosomal circRNA sequencing, large sample validation, and diagnostic model construction revealed that exosomal circ_0043837 and circ_ 0001801were independent predictive factors for LAA stroke, and had better diagnostic efficacy than plasma circRNAs. In the atherosclerotic group (AS), we developed a nomogram for clinical use that integrated the two-circRNA-based risk factors to predict which patients might have the risk of plaque rupture. Circulating exosomal circRNAs profiling identifies novel predictive biomarkers for the LAA stroke and plaque rupture, with superior diagnostic value than plasma circRNAs. It might facilitate the prevention and better management of this disease.

Quantitative Ultrasound of Phalanx in Primary and Secondary Osteoporosis: Mini-review and Practical Experience

Objective: Dual x-ray absorptiometry (DXA) is gold standard of bone densitometry, but quantitative ultrasound (QUS) of bone is less expensive and portable. This study was designed to assess its usefulness in secondary osteoporosis diagnosis. Materials and Methods: There were 200 secondary osteoporosis cases (rheumatoid arthritis, hemodialysis, kidney transplant patients, and levothyroxine users) and of those, their phalanx QUS results were compared with normal controls. Also, the QUS and DXA results were compared to find any correlation of these methods for diagnosing osteoporosis. Results: There was not significantly different results compared with normal controls, except for those of hemodialysis patients ( P = .00). Also, the comparison of QUS with DXA results showed no significant correlation except in hemodialysis patients, in both spinal and femoral regions ( P = .023 and .21, respectively), as well as the levothyroxine group’s spinal region ( P = .005). Conclusion: These results suggest that QUS of phalanx may be useful in screening secondary osteoporosis but for establishment of diagnosis, DXA measurements are still needed.

Proprioception and neuromuscular control at return to sport after ankle surgery with the modified Broström procedure

The modified Broström procedure (MBP) is an initial treatment for symptomatic chronic ankle instability (CAI) patients. This study aimed to compare the proprioception and neuromuscular control ability of both affected and unaffected ankles at the time of return to sports after MBP for patients with scores of normal controls. 75 individuals (40 who underwent MBP, 35 normal controls) participated. The dynamic balance test scores were significantly higher in the affected ankle of the patients than in the controls (1.5 ± 0.6° vs. 1.1 ± 0.4°, p < 0.003). The time to peak torque for dorsiflexion (60.8 ± 13.9 ms vs. 52.2 ± 17.5 ms, p < 0.022) and eversion (68.9 ± 19.1 ms vs. 59.3 ± 21.1 ms, p < 0.043) was significantly delayed in the affected ankle of the patients than in the controls. The dynamic balance test and time to peak torque in CAI patients remained significantly reduced at the time of return-to-sport after MBP. Clinicians and therapists should be aware of potential deficits in proprioception and neuromuscular control when determining the timing of return to sports after MBP.

Identification of Serum Biomarkers in Patients with Alzheimer’s Disease by 2D-DIGE Proteomics

<b><i>Aim:</i></b> The aim of this study is to identify potential serum biomarkers of Alzheimer’s disease (AD) for early diagnosis and to evaluate these markers on a large cohort. <b><i>Methods:</i></b> We performed two-dimensional difference gel electrophoresis to compare the serum of AD patients and normal controls. Western blot or enzyme-linked immunosorbent assay (ELISA) was used to identify the expression levels of proteins. <b><i>Results:</i></b> In this study, a total of 13 differentially expressed proteins were identified. Among them, 2 proteins (inter-alpha-trypsin inhibitor heavy chain H4 [ITI-H4], Apolipoprotein A-IV) were validated by Western blot and 4 proteins (Cofilin 2, Tetranectin, Zinc-alpha-2-glycoprotein [AZGP1], Alpha-1-microglobulin/bikunin precursor [AMBP]) were validated by ELISA, respectively. Western blot results showed that the full size of the ITI-H4 protein was increased, while a fragment of ITI-H4 was decreased in AD patients. In contrast, 1 fragment of Apo A-IV was mainly found in control group and rare to be detected in AD patients. On the other hand, ELISA results showed that Cofilin 2, Tetranectin, AZGP1, and AMBP were significantly increased in AD patients, and Cofilin 2 is strongly correlated with the Mini-Mental State Examination scores of the AD patients. Serum Cofilin 2 was unchanged in Parkinson disease patients as compared to the control group, indicating a specific correlation of serum Cofilin 2 with AD. Moreover, Cofilin 2 was increased in both the serum and brain tissue in the APP/PS1 transgenic mice. <b><i>Conclusion:</i></b> Our study identified several potential serum biomarkers of AD, including: ITI-H4, ApoA-IV, Cofilin 2, Tetranectin, AZGP1, and AMBP. Cofilin 2 was upregulated in different AD animal models and might play important roles in AD pathology.

Altered Functional Mitochondrial Protein Levels in Plasma Neuron-Derived Extracellular Vesicles of Patients With Gadolinium Deposition

The retention of the heavy metal, gadolinium, after a Gadolinium-Based Contrast Agent-assisted MRI may lead to a symptom cluster termed Gadolinium Deposition Disease. Little is known of the disorder’s underlying pathophysiology, but a recent study reported abnormally elevated serum levels of pro-inflammatory cytokines compared to normal controls. As a calcium channel blocker in cellular plasma and mitochondrial membranes, gadolinium also interferes with mitochondrial function. We applied to sera from nine Gadolinium Deposition Disease and two Gadolinium Storage Condition patients newly developed methods allowing isolation of plasma neuron-derived extracellular vesicles that contain reproducibly quantifiable levels of mitochondrial proteins of all major classes. Patients’ levels of five mitochondrial functional proteins were statistically significantly lower and of two significantly higher than the levels in normal controls. The patterns of differences between study patients and controls for mitochondrial dynamics and mitochondrial proteins encompassing neuronal energy generation, metabolic regulation, ion fluxes, and survival differed from those seen for patients with first episode psychosis and those with Major Depressive Disorder compared to their controls. These findings suggest that mitochondrial dysfunction due to retained gadolinium may play a role in causing Gadolinium Deposition Disease. Larger samples of both GDD and GSC patients are needed to allow not only testing the repeatability of our findings, but also investigation of relationships of specific mitochondrial protein deficiencies or excesses and concurrent cytokine, genetic, or other factors to GDD’s neurological and cognitive symptoms. Studies of neuronal mitochondrial proteins as diagnostic markers or indicators of treatment effectiveness are also warranted.

NMR-Based Metabolomic Analysis of Sera in Mouse Models of CVB3-Induced Viral Myocarditis and Dilated Cardiomyopathy

Viral myocarditis (VMC) is an inflammatory heart condition which can induce dilated cardiomyopathy (DCM). However, molecular mechanisms underlying the progression of VMC into DCM remain exclusive. Here, we established mouse models of VMC and DCM by infecting male BALB/c mice with Coxsackievirus B3 (CVB3), and performed NMR-based metabonomic analyses of mouse sera. The mouse models covered three pathological stages including: acute VMC (aVMC), chronic VMC (cVMC) and DCM. We recorded 1D 1H-NMR spectra on serum samples and conducted multivariate statistical analysis on the NMR data. We found that metabolic profiles of these three pathological stages were distinct from their normal controls (CON), and identified significant metabolites primarily responsible for the metabolic distinctions. We identified significantly disturbed metabolic pathways in the aVMC, cVMC and DCM stages relative to CON, including: taurine and hypotaurine metabolism; pyruvate metabolism; glycine, serine and threonine metabolism; glycerolipid metabolism. Additionally, we identified potential biomarkers for discriminating a VMC, cVMC and DCM from CON including: taurine, valine and acetate for aVMC; glycerol, valine and leucine for cVMC; citrate, glycine and isoleucine for DCM. This work lays the basis for mechanistically understanding the progression from acute VMC to DCM, and is beneficial to exploitation of potential biomarkers for prognosis and diagnosis of heart diseases.

Characteristics of Cortical Atrophy and White Matter Lesions Between Dementia With Lewy Bodies and Alzheimer's Disease: A Case-Control Study

Introduction: Currently, there is still clinical overlap between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) patients, which may affect the accuracy of the early diagnosis of DLB. For better diagnosis and prognosis, further exploration of local cortical atrophy patterns and white matter lesions is needed.Methods: We reviewed the outpatient medical records of 97 DLB patients and 173 AD patients from January 2018 to September 2020 along with 30 matched outpatient clinic normal elderly people. MRI visual rating scales, including medial temporal lobe atrophy (MTA), global cortical atrophy-frontal subscale (GCA-F), posterior atrophy (PA), Fazekas scale, Evans Index and cerebral microbleeds were evaluated and analyzed in DLB and AD patients with different severities and normal controls.Results: Overall, patients with DLB had higher scores on all visual rating scales than the normal controls. Meanwhile, compared with AD, DLB had lower MTA scores in the mild to moderate groups (both p ≤ 0.001), but the GCA-F and PA scores were similar (all p &gt; 0.05). The Fazekas scores in the moderate to severe DLB group were lower than those in the AD group (p = 0.024 and p = 0.027, respectively). In addition, the diagnostic performance and sensitivity of multiple imaging indicators for DLB were better than that of MTA alone (the combination of MTA, GCA-F, PA, Fazekas visual rating scales, AUC = 0.756, 95%CI: 0.700–0.813, sensitivity = 0.647, specificity = 0.804 and MTA visual rating scale, AUC = 0.726, 95%CI: 0.667–0.785, sensitivity = 0.497, specificity = 0.876, respectively).Conclusion: The medial temporal lobe of DLB patients was relatively preserved, the frontal and parietal lobes were similarly atrophied to AD patients, and the white matter hyperintensity was lighter than that in AD patients. Combined multiple visual rating scales may provide a novel idea for the diagnosis of early DLB.

Multi-Modal Feature Selection with Feature Correlation and Feature Structure Fusion for MCI and AD Classification

Feature selection for multiple types of data has been widely applied in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) classification research. Combining multi-modal data for classification can better realize the complementarity of valuable information. In order to improve the classification performance of feature selection on multi-modal data, we propose a multi-modal feature selection algorithm using feature correlation and feature structure fusion (FC2FS). First, we construct feature correlation regularization by fusing a similarity matrix between multi-modal feature nodes. Then, based on manifold learning, we employ feature matrix fusion to construct feature structure regularization, and learn the local geometric structure of the feature nodes. Finally, the two regularizations are embedded in a multi-task learning model that introduces low-rank constraint, the multi-modal features are selected, and the final features are linearly fused and input into a support vector machine (SVM) for classification. Different controlled experiments were set to verify the validity of the proposed method, which was applied to MCI and AD classification. The accuracy of normal controls versus Alzheimer’s disease, normal controls versus late mild cognitive impairment, normal controls versus early mild cognitive impairment, and early mild cognitive impairment versus late mild cognitive impairment achieve 91.85 ± 1.42%, 85.33 ± 2.22%, 78.29 ± 2.20%, and 77.67 ± 1.65%, respectively. This method makes up for the shortcomings of the traditional multi-modal feature selection based on subjects and fully considers the relationship between feature nodes and the local geometric structure of feature space. Our study not only enhances the interpretation of feature selection but also improves the classification performance, which has certain reference values for the identification of MCI and AD.

Autoantibody to GNAS in Early Detection of Hepatocellular Carcinoma: A Large-Scale Sample Study Combined with Verification in Serial Sera from HCC Patients

The aim of this study was to explore the value of autoantibody to GNAS in the early detection of hepatocellular carcinoma (HCC). In a large-scale sample set of 912 participants (228 cases in each of HCC, liver cirrhosis (LC), chronic hepatitis B (CHB), and normal controls (NCs) groups), autoantibody to GNAS was detected with a positive result in 47.8% of HCC patients, which was significantly higher than that in patients with LC (35.1%), CHB (19.7%), and NCs (19.7%). Further analysis showed that the frequency of autoantibody to GNAS started increasing in compensated cirrhosis patients (37.0%) with a jump in decompensated cirrhosis patients (53.2%) and reached a peak in early HCC patients (62.4%). The increasing autoantibody response to GNAS in patients at different stages was closely associated with the progression of chronic liver lesions. The result from 44 human serial sera demonstrated that 5 of 11 (45.5%) HCC patients had elevated autoantibody to GNAS before and/or at diagnosis of HCC. Moreover, 46.1% and 62.4% of high positive rates in alpha-fetoprotein (AFP) negative and early-stage HCC patients can supplement AFP in early detection of HCC. These findings suggest that autoantibody to GNAS could be used as a potential biomarker for the early detection of HCC.

Associations Among Diffusion Tensor Image Along the Perivascular Space (DTI-ALPS), Enlarged Perivascular Space (ePVS), and Cognitive Functions in Asymptomatic Patients With Carotid Plaque

Background and Aim: Carotid atherosclerosis (CAS) is a common pathogenesis of cerebrovascular disease closely related to stroke and silent cerebrovascular disease (SCD), while the insufficient brain perfusion mechanism cannot quite explain the mechanism. The purpose of this study was to utilize diffusion tensor image analysis along the perivascular space (DTI-ALPS) to evaluate the glymphatic system activity and correlated DTI-ALPS with enlarged perivascular spaces (ePVS), carotid intima-media thickening (CIMT), mini-mental state examination (MMSE), and serological indicator in individuals with carotid plaque.Methods: Routine MRI and diffusion tensor images scan of the brain, carotid ultrasound, and blood examination were conducted on 74 individuals (52 carotid plaque subjects, 22 non-carotid plaque subjects), whose demographic and clinical characteristics were also recorded. DTI-ALPS index between patients with carotid plaque and normal controls were acquired and the correlations with other variables were analyzed.Results: The values of ALPS-index in the carotid plaque group was significantly lower compared to normal controls (2.12 ± 0.39, 1.95 ± 0.28, respectively, p = 0.034). The ALPS-index was negatively correlated with the basal ganglia (BG)-ePVS score (r = −0.242, p = 0.038) while there was no significant difference in the centrum semiovale (CSO)-ePVS score. Further analysis showed that there are more high-grade ePVS in the BG compared to the carotid plaque group than in the non-carotid plaque group (84.6% vs. 40.9%, p = 0.001).Conclusions: ALPS-index reflects the glymphatic system of the brain, which is associated with early high-risk cerebrovascular diseases. There may be damage in the function of the glymphatic system which induces the expansion of the perivascular space (PVS) in the BG in individuals with carotid plaque.